The emergence and worldwide dissemination of antibiotic resistant organisms represents a significant threat to global public health. An organism that epitomizes both the urgency and challenges associated with this threat is carbapenem-resistant Klebsiella pneumoniae (CRKP). CRKP was first observed in a clinical case in 1996 in a hospital in North Carolina. Since that time, successful lineages of CRKP have spread across the globe, becoming endemic in healthcare networks in many regions. This increasing prevalence of CRKP poses a great risk to hospitalized patients, as crude mortality rates for CRKP infections can be upwards of 50%. Moreover, the threat associated with CRKP continues to escalate, with numerous reports of CRKP that are resistant to even last-line antibiotics, leaving affected patients with limited treatment options. The seriousness of the CRKP epidemic has led to both the U.S. Centers for Disease Control and the World Health Organization ranking it as their most urgent antibiotic resistant threat. However, despite the attention given to CRKP, it remains highly prevalent in many areas. Our central hypothesis is that our inability to effectively control CRKP, as well as other urgent antibiotic resistant threats, is due to a lack of understanding of the clinical and epidemiologic factors that drive the emergence and spread of antibiotic resistant organisms across regional healthcare networks. Here, we seek to overcome this knowledge gap by first applying whole-genome sequencing to construct regional transmission networks for CRKP, and then overlaying rich epidemiologic and clinical meta-data to identify drivers of transmission, resistance evolution and infection across regional healthcare facilities. These goals will be accomplished through the following three aims: 1) apply phylogenetic methods to reconstruct regional transmission networks, and perform data analysis and modeling to identify drivers of transmission within and between hospitals, 2) identify genetic determinants of resistance to last line antibiotics and analyze in the context of the regional transmission network and clinical metadata to identify factors associated with both the evolution and acquisition of resistance and 3) identify genetic determinants associated with CRKP infection and analyze in the context of the regional transmission networks and patient meta-data to identify virulent sub-lineages and convergent variation that are associated with poor patient outcomes. The totality of these aims will provide critical insight into the factors driving transmission, resistance evolution and infection with CRKP as it spreads across regional healthcare networks. Moreover, we believe our approach of integrating genomic, clinical and epidemiologic data to study the proliferation of antibiotic resistant threats at a regional level can be applied in other contexts to help guide regional infection prevention.